Artur Shvetcov, Shannon Thomson, Mark E. Graham, Brittany Hauger, Jessica Keller, Christine Smoyer, Sarah E. Tague, Ann‐Na Cho, Farhad Imam, Varsha Krish, Matthew K. Taylor, Jonathan D. Mahnken, Debra K. Sullivan, Joanne H. Reed, Jeffrey M. Burns, Chad Slawson, Russell H. Swerdlow, Heather M. Wilkins, Caitlin A. Finney
Abstract INTRODUCTION Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for late‐onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. METHODS Here, we integrate proteomic profiling of plasma ( n = 9028), cerebrospinal fluid ( n = 1099), dorsolateral prefrontal cortex ( n = 720), and superior temporal gyrus ( n = 105) to define the immune phenotype associated with APOE ε4. RESULTS We identify a conserved, allele dose‐dependent pro‐inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient‐derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype‐driven mechanism. Cross‐tissue comparisons reveal shared innate and antiviral responses alongside tissue‐specific immune signaling. Notably, a 12‐week medical ketogenic diet partially reversed the APOE ε4 immune signature. DISCUSSION These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.